Aquaporin-4 mis-localization slows glymphatic clearance of α-synuclein and promotes α-synuclein pathology and aggregate propagation

Sep 4, 2024bioRxiv : the preprint server for biology

Misplacement of water channels slows brain waste clearance of alpha-synuclein and promotes its build-up and spread

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Abstract

Neocortical α-synuclein pathology was found to be associated with AQP4 mis-localization throughout the gray matter.

Misfolded α-synuclein aggregates are linked to neurodegenerative diseases, including Alzheimer's and Parkinson's.
Sleep disruption may contribute to the accumulation of these harmful proteins and is often an early symptom of neurodegenerative disorders.
Loss of perivascular AQP4 localization is suggested to impair the clearance of α-synuclein, potentially facilitating its spread to neighboring cells.
In a transgenic mouse model, impaired glymphatic clearance of α-synuclein was observed due to AQP4 mis-localization.
Increased α-synuclein aggregates were noted in a mouse model after the loss of perivascular AQP4 localization, indicating a potential mechanism for disease progression.

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The appearance of misfolded and aggregated proteins is a pathological hallmark of numerous neurodegenerative diseases including Alzheimer's disease and Parkinson's disease. Sleep disruption is proposed to contribute to these pathological processes and is a common early feature among neurodegenerative disorders. Synucleinopathies are a subclass of neurodegenerative conditions defined by the presence of α-synuclein aggregates, which may not only enhance cell death, but also contribute to disease progression by seeding the formation of additional aggregates in neighboring cells. The mechanisms driving intercellular transmission of aggregates remains unclear. We propose that disruption of sleep-active glymphatic function, caused by loss of precise perivascular AQP4 localization, inhibits α-synuclein clearance and facilitates α-synuclein propagation and seeding. We examined human post-mortem frontal cortex and found that neocortical α-synuclein pathology was associated with AQP4 mis-localization throughout the gray matter. Using a transgenic mouse model lacking the adapter protein α-syntrophin, we observed that loss of perivascular AQP4 localization impairs the glymphatic clearance of α-synuclein from intersititial to cerebrospinal fluid. Using a mouse model of α-synuclein propogation, using pre-formed fibril injection, we observed that loss of perivascular AQP4 localization increased α-synuclein aggregates. Our results indicate α-synuclein clearance and propagation are mediated by glymphatic function and that AQP4 mis-localization observed in the presence of human synucleinopathy may contribute to the development and propagation of Lewy body pathology in conditions such as Lewy Body Dementia and Parkinson's disease.

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Aquaporin-4 mis-localization slows glymphatic clearance of α-synuclein and promotes α-synuclein pathology and aggregate propagation

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